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CD40: A Mediator of Pro- and Anti-Inflammatory Signals in Renal Tubular Epithelial Cells

Sreenivas Laxmanan^*,,, Dipak Datta^*,,, Christopher Geehan^*,,, David M. Briscoe^*,, and Soumitro Pal^*,,

^* Division of Nephrology; Transplantation Research Center, Children’s Hospital Boston and Brigham and Women’s Hospital; and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

Address correspondence to: Dr. Soumitro Pal, Division of Nephrology, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115. Phone: 617-919-2989; Fax: 617-730-0130; soumitro.pal{at}childrens.harvard.edu

Received for publication January 11, 2005. Accepted for publication June 14, 2005.

Infiltration of immune cells into the renal interstitium is characteristic of chronic inflammatory kidney diseases. CD4⁺ T cells and platelets express CD40 ligand (CD40L) and are reported to mediate proinflammatory events in renal proximal tubular epithelial cells (RPTEC) via interaction with CD40. In other cell types, CD40 signals can also induce protective genes. Here, human RPTEC were treated with sCD40L to ligate CD40, and a significant increase in the generation of proinflammatory reactive oxygen species was found; however, CD40-activated cells did not undergo apoptosis. This suggests that CD40 signals may simultaneously induce antiapoptotic genes for cytoprotection of RPTEC. Heme oxygenase-1 (HO-1) expressed in RPTEC serves as a protective gene, but it is not known whether it is regulated by CD40. Next, RPTEC were transiently transfected with a full-length HO-1 promoter-luciferase construct and were treated with sCD40L. CD40 ligation was found to significantly increase HO-1 promoter activity. By electrophoretic mobility shift assay, it was confirmed that CD40 signaling induced the transcriptional activation of HO-1 through the binding of NF-B to its promoter. By Western blot analysis, a marked increase in HO-1 protein expression following CD40 ligation was also found. These observations are of clinical significance because it was found that CD40 and HO-1 are induced in expression in vivo in inflamed rejecting kidney biopsies and co-expressed in renal tubules. Therefore, ligation of CD40 in RPTEC promotes both inflammatory and anti-inflammatory processes. Regulating the balance between these two events may be of importance in the prevention of tubular injury associated with renal disease.

This article has been cited by other articles:

				D. Datta, O. Dormond, A. Basu, D. M. Briscoe, and S. Pal Heme oxygenase-1 modulates the expression of the anti-angiogenic chemokine CXCL-10 in renal tubular epithelial cells Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1222 - F1230. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673